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. 2022 Apr;36(4):956-969.
doi: 10.1038/s41375-022-01512-5. Epub 2022 Feb 2.

CDK19 regulates the proliferation of hematopoietic stem cells and acute myeloid leukemia cells by suppressing p53-mediated transcription of p21

Zihao Zhang #  1 , Yukai Lu #  1 , Yan Qi  1 , Yang Xu  1 , Song Wang  1 , Fang Chen  1 , Mingqiang Shen  1 , Mo Chen  1 , Naicheng Chen  1 , Lijing Yang  1 , Shilei Chen  1 , Fengchao Wang  1 , Yongping Su  1 , Mengjia Hu  2   3 , Junping Wang  4
Affiliations

CDK19 regulates the proliferation of hematopoietic stem cells and acute myeloid leukemia cells by suppressing p53-mediated transcription of p21

Zihao Zhang et al. Leukemia. 2022 Apr.

Abstract

The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19-/- HSCs exhibit similar phenotypes to those of cells treated with SenexinB. Interestingly, the p53 signaling pathway is significantly activated in HSCs lacking CDK19 expression. Further investigations show that CDK19 can interact with p53 to inhibit p53-mediated transcription of p21 in HSCs and treatment with a specific p53 inhibitor (PFTβ) partially rescues the defects of CDK19-null HSCs. Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.

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